CN115925718A

CN115925718A - Tetracyclic lactam derivative and application thereof

Info

Publication number: CN115925718A
Application number: CN202211715063.6A
Authority: CN
Inventors: 郝欣; 王中利; 罗志阳
Original assignee: Ruishi Biomedical Co ltd
Current assignee: Ruishi Biomedical Co ltd
Priority date: 2022-12-27
Filing date: 2022-12-27
Publication date: 2023-04-07

Abstract

The present disclosure relates to tetracyclic lactam derivatives and uses thereof. In particular to a compound shown as a formula I or a pharmaceutically acceptable salt thereof, wherein R is ¹ ～R ⁶ M, n, o, p and ring a are as defined herein.

Description

Tetracyclic lactam derivative and application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a tetracyclic lactam derivative and application thereof.

Background

Mitogen-activated protein kinase 2 (MAPKAP K2 or MK 2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines such as tumor necrosis factor α (TNF- α), interleukin 6 (IL-6) and interferon γ (IFN γ), which are involved in many acute and chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease.

Some known MK2 inhibitors have been synthesized, and such molecules have been shown to exhibit selectivity for other kinases, including, for example, CDK 2. For example, bioorg.med.chem.lett.19 (2009) 4882-4884 discloses

WO2016044463 discloses another class of MK2 inhibitors, representative molecules are as follows,

in addition, other tetracyclic lactam derivative MK2 inhibitors have been successively reported, such as WO2014149164, WO2009010488, WO2018170204, WO2018170200, WO2018170201 and the like, however, no MK2 inhibitor is currently on the market, and the compounds of the present disclosure are not disclosed in any literature, and exhibit specific MK2 inhibitory effects and selectivity for other kinases (including, for example, CDK 2).

Disclosure of Invention

The disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof

Wherein ring A is selected from a 5-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O or S;

R ¹ each independently selected from halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^1A Substituted, R ^1A Each independently of the otherIs selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ² and R ³ Independently selected from hydrogen or C _1-6 Alkyl optionally substituted with one or more groups selected from halo, hydroxy, cyano or amino;

R ⁴ each independently selected from halogen, oxo (= O), hydroxy, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with one or more R ^4A Substituted;

R ^4A each independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl being optionally substituted with one or more R ^4B Substituted, R ^4B Each independently selected from halogen, hydroxy, oxo, C _1-6 Alkyl radical, C _1-6 An alkoxy group;

R ⁵ each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^2A Substituted, R ^2A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ⁶ each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^3A Substituted, R ^3A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

m is selected from an integer between 0 and 4;

n is selected from an integer between 0 and 4;

o and p are each selected from integers between 0 and 2.

In some embodiments, ring a in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a 5-membered heterocyclic ring containing 1-2 heteroatoms. Exemplary structures for ring a are as follows (without limitation):

wherein R is ⁴ M is as defined above.

In some embodiments, ring A in the compound of formula I or a pharmaceutically acceptable salt thereof is selected from

Or

Or->

Or

Or

Or

In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁵ Each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^2A Substituted, R ^2A As defined above.

In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁵ Each independently selected from 3 to 6 membered cycloalkyl optionally substituted with 1-3R ^2A Substituted, R ^2A As defined above.

In another aspect, some embodiments provide that o is selected from 0 or 1 in the compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁶ Each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^3A Substituted, R ^3A As defined above.

In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁶ Each independently selected from 3 to 6 membered cycloalkyl optionally substituted with 1-3R ^3A Substituted, R ^3A As defined above.

In other embodiments, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, wherein p is selected from 0 or 1.

In another aspect, R in the compound of formula I or a pharmaceutically acceptable salt thereof ³ Selected from hydrogen.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ² Is selected from C _1-6 Alkyl optionally substituted with 1-3 substituents selected from halogen, hydroxy or amino. Further, in other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ² Selected from methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ² Selected from hydrogen.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from halogen, hydroxy, amino or cyano.

In some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ¹ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^1A And (4) substitution. Further, in other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ¹ Selected from methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl.

In another aspect, R in the compound of formula I or a pharmaceutically acceptable salt thereof ¹ Each independently selected from 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl or alkoxy being optionally substituted with 1-3R ^1A Substituted, R ^1A As defined above.

Further, in some embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁴ Each independently selected from halogen, oxo (= O), hydroxy or amino.

In other embodiments, R in the compound of formula I or a pharmaceutically acceptable salt thereof ⁴ Each independently selected from C _1-6 Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl optionally substituted with 1-3R ^4A Substituted, R ^4A As defined above.

Further, the compound represented by the formula I or a pharmaceutically acceptable salt thereof is:

wherein R is ¹ 、R ² 、R ⁴ Ring a is as defined above.

In some embodiments, a compound of formula I or formula II or a pharmaceutically acceptable salt thereofIn salt R ^1A Each independently selected from halogen, hydroxy or amino. In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof ^1A Each independently selected from fluorine or chlorine.

In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof ^4A Each independently selected from halogen, cyano, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl optionally substituted with 1-3R ^4B Substituted, R ^4B As defined above.

In other embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof ^4A Each independently selected from halogen, cyano or C _1-6 Alkoxy, preferably fluoro, chloro, cyano, methyl, ethyl, difluoromethyl or trifluoromethyl.

The compound shown in the formula II or the medicinal salt thereof has the following general structure:

wherein R is ¹ 、R ² 、R ⁴ And m is as defined for formula I.

In some embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof ^4B Each independently selected from halogen, C _1-6 Alkyl or C _1-6 An alkoxy group. In other embodiments, R in the compound of formula I or formula II or a pharmaceutically acceptable salt thereof ^4B Each independently selected from halogen or C _1-6 Alkyl, more preferably fluoro, chloro, methyl, ethyl, difluoromethyl or trifluoromethyl.

Typical compounds of formula I, or pharmaceutically acceptable salts thereof, include, but are not limited to:

/>

or>

In some embodiments, a compound of formula I, or a pharmaceutically acceptable salt thereof, comprises:

/>

in another aspect, the present disclosure also provides a method of preparing a compound of formula I, or a pharmaceutically acceptable salt thereof, comprising the step of coupling a compound of formula A with a compound of formula B under metal catalysis,

wherein X ¹ Is a leaving group selected from, but not limited to, halogen such as chloro; x ² Is hydrogen or a borate group.

In some embodiments, the metal catalyst in the foregoing reaction is selected from, but not limited to, metallic palladium, such as a divalent palladium catalyst (not limited to palladium acetate). On the other hand, an appropriate base may be added to the coupling reaction to ensure that the reaction proceeds more smoothly. In some embodiments, the base is selected from, but not limited to, an organic base or an inorganic base, such as sodium tert-butoxide.

The present disclosure also provides isotopic substitutions of the foregoing compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substituent is a deuteron.

The compounds of the present disclosure have excellent inhibitory effects on MK2 kinase activity in vitro. In some embodiments, the disclosed compounds have an IC50 for MK2 kinase inhibition between 0.01 and 100nM. In some embodiments, the disclosed compounds have an IC50 for MK2 kinase inhibition between 0.01 and 50nM. In some embodiments, the disclosed compounds have an IC50 for MK2 kinase inhibition between 1 and 20nM. In some embodiments, compounds of the disclosure have an IC50 for MK2 kinase inhibition between 0.1 and 10nM.

The present disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof, or an isotopic substitute of the compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000mg.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopically substituted version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or isotopic substitution thereof.

In certain embodiments, the pharmaceutical composition comprises from 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.

The present disclosure also provides a method for preventing and/or treating a patient having an MK2 mediated disease or condition by administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or isotopic substitution thereof, or a pharmaceutical composition thereof.

In some embodiments, the MK 2-mediated disease or disorder is selected from an autoimmune disorder, an inflammatory disorder, a cancer, a fibrotic disorder, or a metabolic disorder.

The present disclosure also provides a method of preventing and/or treating a patient suffering from a systemic immune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder, comprising administering to the patient a therapeutically effective amount of a compound of formula I as set forth above or a pharmaceutically acceptable salt or isotopic substitution thereof, or a pharmaceutical composition as set forth above.

The disclosure also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, in the preparation of a medicament for the prevention and/or treatment of an MK2 mediated disease or condition. In some embodiments, the MK2 mediated disease or disorder is preferably a systemic immune disorder, an inflammatory disorder, a cancer, a fibrotic disorder, or a metabolic disorder.

The present disclosure also provides the use of a compound represented by formula I as described above or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described above in the manufacture of a medicament for the prevention and/or treatment of a autoimmune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder.

The pharmaceutically acceptable salts of the compounds described in this disclosure may be selected from inorganic or organic salts.

The disclosed compounds may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

In the chemical structures of the compounds described in this disclosure, the bond "/" represents an unspecified configuration, i.e., if a chiral isomer is present in the chemical structure, the bond "/" may be

Or->

Or both>

And &>

Two configurations.

In the chemical structure of the compounds described in this disclosure, a bond

The configuration is not specified, i.e. it can be in the Z or E configuration, or bothTwo configurations are contemplated.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. An example of a lactam-lactam equilibrium is between A and B as shown below.

All compounds in this disclosure can be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The nomenclature of the compounds does not exclude any tautomers.

The present disclosure also includes certain isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹³ N、 ¹⁵ N、 ¹⁵ O、 ¹⁷ O、 ¹⁸ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F、 ¹²³ I、 ¹²⁵ I and ³⁶ cl, and the like.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance. The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. The person skilled in the art is able to synthesize the compounds of formula (I) in deuterated form with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, tri-deuterated boranes tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "optionally halogen-or cyano-substituted C _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

Interpretation of terms:

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.

"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.

The "effective amount" or "therapeutically effective amount" described in this disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being further optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano or amino.

The term "cycloalkyl" or "carbocyclic ring" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being further optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano or amino. The term "heterocycloalkyl" or "heterocycle"Refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 6 ring atoms, non-limiting examples of "heterocycloalkyl" include:

or->

And so on.

Heterocycloalkyl may be optionally substituted or unsubstituted and when substituted, the substituents are preferably one or more groups independently selected from halo, hydroxy, oxo, nitro, cyano, amino, C1-6 alkyl, C1-6 alkoxy, 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being further optionally substituted by one or more groups selected from halo, hydroxy, oxo, nitro, cyano or amino. The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 3 heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-membered. For example. Non-limiting examples thereof include:

or

And so on.

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, oxo (= O), hydroxy, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, wherein the 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl is optionally substituted, optionally selected from halogen, hydroxy, oxoAnd (3) substituted, nitro, cyano or amino.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl further optionally substituted with one or more groups selected from halo, hydroxy, oxo, nitro, cyano or amino.

The term "hydroxy" refers to an-OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "cyano" refers to — CN.

The term "amino" refers to the group-NH ₂ 。

The term "nitro" means-NO ₂ 。

The term "oxo" refers to an = O substituent.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured by Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated Methanol (Methanol-d) ₄ ) Internal standard is Tetramethylsilane (TMS).

The HPLC assay used an Agilent1100 HPLC, GAS15B DAD uv detector, water Vbridge C18 x 4.6mm 5um column.

MS was measured using an Agilent6120 triple quadrupole mass spectrometer, G1315D DAD detector, waters Xbridge C18.6 x 50mm,5um chromatography column, scanning in positive/negative ion mode with a mass scan range of 80-1200.

The silica gel plate for thin layer chromatography is HSGF254 silica gel plate of cigarette platform yellow sea, and the silica gel plate for Thin Layer Chromatography (TLC) is 0.2mm + -0.03 mm, and the specification of the product for thin layer chromatography separation and purification is 0.4mm-0.5mm.

The flash column purification system used either Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

The forward column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel of Taiwan yellow sea as carrier, or uses the ultra-pure forward phase silica gel column (40-63 μm,60g,24g,40g,120g or other specifications) pre-filled by Santai in Changzhou.

Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan technology, ABCR GmbH & Co. KG, acros Organics, aldrich Chemical Company, shao Yuan Chemical technology (Accela ChemBio Inc), biddy medicine, and the like.

In the examples, the reactions were all carried out under a nitrogen atmosphere without specific indication.

Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1L volume.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogen is prepared by QPH-1L type hydrogen generator of Shanghai Quanpu scientific instruments company.

The nitrogen atmosphere or the hydrogen atmosphere is usually evacuated, and nitrogen or hydrogen is charged, and the operation is repeated 3 times.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the reaction progress in the examples employs Thin Layer Chromatography (TLC), a developing agent used for the reaction, an eluent system for column chromatography used for purifying a compound, and a developing agent system for thin layer chromatography, and the volume ratio of a solvent is adjusted according to the polarity of the compound, and may also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

Step 1: synthesis of compound 1 b:

to a 100-mL single-neck flask were added, in order, compound 1a (1.00g, 4.95mmol), dioxane (15 mL), pinacol diborate (1.9mL, 7.4mmol), potassium acetate (0.970g, 9.90mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.29g, 0.50mmol). Stirring was carried out at 90 ℃ for 2 hours under nitrogen. Cooled to room temperature and filtered. Concentrating under reduced pressure, and purifying the residue by column chromatography (SiO) ₂ 0% -10% ethyl acetate/petroleum ether) to give compound 1b.

¹ H NMR(400MHz,CDCl ₃ )δ7.50(d,J＝3.6Hz,1H),7.13(d,J＝3.6Hz,1H),3.94(s,2H),1.34(s,12H).

LCMS:m/z 518.0(M+H) ⁺ 。

Step 2: synthesis of Compound 1:

to a 50 mL single-necked flask were added compound 1b (39.2mg, 0.1575 mmol), dioxane (5 mL)/water (0.2 mL), (R) -3-chloro-10-methyl-9,10,11,12-tetrahydro-8H- [1,4] diazepinol [5',6":4,5] thieno [3,2-f ] quinolin-8-one (50mg, 0.16mmol, synthesized by reference to the method in patent WO 2018170204), bis-triphenylphosphine palladium dichloride (2.45mg, 0.003mmol), and sodium carbonate (33.4mg, 0.315mmol) in this order at room temperature. Stirring at 90 ℃ for 2 hours under the protection of nitrogen. After cooling to room temperature, the mixture was extracted with ethyl acetate (5 mL. Times.2), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Concentrating under reduced pressure, and preparing into compound 1 by high performance liquid phase (formic acid/acetonitrile/water system).

LCMS:m/z:405.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.18(d,J＝9.2Hz,1H),8.18-8.09(m,3H),7.92-7.89(m,2H),7.18-7.12(m,2H),4.37(s,2H),3.62-3.47(m,3H),1.20(d,J＝6.4Hz,3H).

Example 2

Compound 2 was prepared according to the procedure described in example 1.

LCMS:m/z 389.1(M+H) ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ9.15(d,J＝8.8Hz,1H),8.64(s,1H),8.38(s,1H),8.11-8.06(m,2H),7.97(d,J＝8.8Hz,1H),7.92(d,J＝8.8Hz,1H),7.11(t,J＝5.2Hz,1H),5.60(s,2H),3.70-3.58(m,3H),1.20(d,J＝6.4Hz,3H).

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: in vitro MK2 enzyme activity detection assay

1. Experimental Material

Name (R)	Brand	Goods number/model
			MAPKAPK2	Carna	02-142
P11	GL	117885
			ATP	Sigma	A7699
DMSO	Sigma	D2650
			EDTA	Sigma	E5134
96-well plate	Corning	3365
			384-well plate	Corning	3573

2. Experimental procedure

In vitro MK2 kinase activity was tested by the method of Mobility Shift Assay. In the experiment, test compounds were tested for inhibition of MK2 activity starting at a concentration of 10000nM, 3-fold dilution, 10 concentrations in total, and tested in duplicate wells. The compound PF-3644022 was used as a standard control.

1-fold kinase buffer (50mM HEPES, pH 7.5,0.0015% Brij-35) and stop buffer (100mM HEPES, pH 7.5,0.015% Brij-35,0.2% Coating Reagent #3,50mM EDTA) were prepared. Adding a proper amount of kinase into 1 time of kinase buffer solution to prepare 2.5 times of enzyme solution; compound test concentrations were prepared as 5-fold compound dilutions (1-fold kinase buffer, 10% dmso) corresponding to the test concentrations of the compounds; adding a proper amount of FAM-labeled polypeptide and ATP into 1-time kinase buffer solution to prepare 2.5-time substrate solution. Adding 5 mul of 5-fold compound diluent and 10 mul of 2.5-fold enzyme solution into reaction holes of a 384-hole reaction plate, uniformly mixing, and incubating for 10 minutes at room temperature; then 10. Mu.l of 2.5-fold substrate solution was added to the 384-well plate and centrifuged at 1000rpm for 1 minute; the reaction plate was incubated at 28 ℃ for 60 min; the reaction was stopped by adding 25. Mu.l of stop solution to a 384-well reaction plate and centrifuged at 1000rpm for 1 minute; and finally reading the conversion rate data on a Caliper EZ Reader II.

IC50 values for compounds were fitted with XLFit excel add-in version 5.4.0.8. Fitting formula:

Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。

MK2 kinase Biochemical inhibitory Activity of the Compounds of the disclosure were determined by the above assay, with the IC50 values shown in Table 1

TABLE 1

Numbering	MK2 IC ₅₀ (nM)
		Example 1	1.7
Example 2	6.4

Test example 2: in vitro THP-1 cell line cytokine detection experiment

1. Experimental Material

2. Experimental procedure

In vitro THP-1 cell line assay for cytokines the assay was performed by the method of LPS-induced cell production of the cytokine TNF-. Alpha.. In the experiment, the test starting concentration of the test compound was 10000nM, 3-fold diluted, 10 concentrations in total, and the test was repeated in wells.

THP-1 cells were cultured in flasks at a concentration of 10^6/mL with the addition of 10ng/mL PMA to stimulate differentiation. After 24 hours, cells were collected with Accutase and counted. 0.1million THP-1/0.2mL/well was seeded into 96-well plates and incubated overnight.

The next day, 2-fold compound and 4-fold LPS dilution were prepared. The medium was removed and 50. Mu.l of compound diluent and 50. Mu.l of fresh medium were added to each well at 37 ℃ with 5% CO ₂ And (5) incubating for half an hour. Then 50. Mu.l of compound diluent and 50. Mu.l of LPS diluent (final concentration 500 ng/ml) were added thereto, 5% CO at 37 ℃ ₂ Incubate for 24 hours. The normal control group replaced compound diluent with DMSO, and the experimental control group replaced LPS diluent with culture medium.

The reaction plate was centrifuged at 350g for 5 minutes and 150. Mu.l of the supernatant was collected. The samples were tested for TNF-alpha concentration using an ELISA kit.

Test example 3: in vitro PBMC cell detection cytokine assay

1. Experimental materials

Name (R)	Brand	Goods number/model
			Frozen PBMCs	HemaCare	PB009C-2
RPMI Medium 1640	Gibco	11875093
			FBS	Biological Industries	04-002-1A
Penicillin-Streptomycin(P/S)	Gibco	15140122
			PBS	Biosera	LM-S2041/500
LPS	Sigma	L2880
			CellTiter Glo	Promega	G7573
96-well Flat Bottom Microplate	Corning	3903
			Human TNF-αDuoset ELISA	R&D	DY210

2. Experimental procedure

In vitro PBMC cell assay cytokine assays were tested by LPS-induced cell production of the cytokine TNF-. Alpha.. In the experiment, the test starting concentration of the test compound was 10000nM, 3-fold diluted, 9 concentrations in total, and the test was repeated in wells.

PBMC cells were collected and cell counts and viability calculations were performed. 0.2million PBMC/0.1mL/well were seeded into 96-well plates. Compound and LPS diluent are prepared. Mu.l of compound diluent and 50. Mu.l of LPS diluent (final concentration 0.1 ng/ml) were added to each well at 37 ℃ with 5% CO ₂ Incubate for 24 hours. The normal control group replaced compound diluent with DMSO, and the experimental control group replaced LPS diluent with culture medium.

Collect 120. Mu.l of supernatant. The concentration of TNF-. Alpha.in the samples was tested using ELISA kits.

Add 80. Mu.L to each well

Reagent, detecting cell activity. />

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof

R ¹ each independently selected from halogen, hydroxy, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl being optionally substituted with one or more R ^1A Substituted, R ^1A Each independently selected from halogen, hydroxy, oxo, nitro, cyano or amino;

R ² and R ³ Independently selected from hydrogen or C _1-6 Alkyl optionally substituted with one or more substituents selected from halogen, hydroxy, cyano or amino;

R ⁴ each independently selected from halogen, oxo (= O), hydroxy, nitro, cyano, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally substituted with one or more R ^4A Substituted;

m is selected from an integer between 0 and 4;

n is selected from an integer between 0 and 4;

o and p are each selected from integers between 0 and 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is selected from a 5-membered heterocyclic ring containing 1-2 heteroatoms, preferably:

wherein R is ⁴ M is as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^2A Substituted, R ^2A As defined in claim 1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Each independently selected from 3 to 6 membered cycloalkyl optionally substituted with 1-3R ^2A Substituted, R ^2A As defined in claim 1.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein o is selected from 0 or 1.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Each independently selected from halogen, hydroxy, amino, C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^3A Substituted, R ^3A As defined in claim 1.

7. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Each independently selected from 3 to 6 membered cycloalkyl optionally substituted with 1-3R ^3A Substituted, R ^3A As defined in claim 1.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein p is selected from 0 or 1.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R ³ Selected from hydrogen.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ² Is selected from C _1-6 Alkyl optionally substituted with 1-3 substituents selected from halogen, hydroxy or amino; further, R ² Selected from methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl.

11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R ¹ Selected from halogen, hydroxy, amino or cyano.

13. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R ¹ Is selected from C _1-6 Alkyl or C _1-6 Alkoxy, said alkyl or alkoxy being optionally substituted with 1-3R ^1A Substituted, R ^1A As defined in claim 1; further, R ¹ Selected from methyl, ethyl, hydroxyethyl, difluoromethyl or trifluoromethyl.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R ¹ Each independently selected from 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said alkyl or alkoxy being optionally substituted with 1-3R ^1A Substituted, R ^1A As defined in claim 1.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Each independently selected from halogen, oxo (= O), hydroxy or amino.

16. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Each independently selected from C _1-6 Alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl optionally substituted with 1-3R ^4A Substituted, R ^4A As defined in claim 1.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is

Wherein R is ¹ 、R ² 、R ⁴ Ring A, m are as defined in claim 1.

18. The compound according to claim 1 or 17, or a pharmaceutically acceptable salt thereof, wherein R ^1A Each independently selected from halogen, hydroxy or amino, preferably fluorine or chlorine.

19. The compound according to claim 1 or 17, or a pharmaceutically acceptable salt thereof, wherein R ^4A Each independently selected from halogen, cyano, C _1-6 Alkoxy, 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl, said 3-to 6-membered cycloalkyl or 3-to 6-membered heterocycloalkyl optionally substituted with 1-3R ^4B Substituted, R ^4B As defined in claim 1; further, R ^4A Preferably halogen, cyano or C _1-6 An alkoxy group.

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, which is

Wherein R is ¹ 、R ² 、R ⁴ And m is as defined in claim 1.

21. The compound of claim 1 or 20, wherein R ^4B Each independently selected from halogen, C _1-6 Alkyl or C _1-6 Alkoxy, preferably halogen or C _1-6 Alkyl, more preferably fluoro, chloro, methyl, ethyl, difluoromethyl or trifluoromethyl.

22. A compound of formula I or a pharmaceutically acceptable salt thereof, which is

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23. A compound of formula I or a pharmaceutically acceptable salt thereof, which is

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24. An isotopic substitution of the compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, preferably, the isotopic substitution is deuterium.

25. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or an isotopic substitution of claim 24, and a pharmaceutically acceptable excipient.

26. A method of preventing and/or treating a patient having an MK2 mediated disease or condition by administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to claim 24, or a pharmaceutical composition according to claim 25.

27. A method of preventing and/or treating a patient having an autoimmune disorder, an inflammatory disorder, cancer, a fibrotic disorder or a metabolic disorder by administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or an isotopic substitution according to claim 24, or a pharmaceutical composition according to claim 25.

28. Use of a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt thereof, or an isotopic substitution of claim 24, or a pharmaceutical composition of claim 25, in the manufacture of a medicament for the prevention and/or treatment of a condition mediated by MK 2.

29. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or an isotopic substitution of claim 24, or a pharmaceutical composition of claim 25, in the manufacture of a medicament for the prevention and/or treatment of an autoimmune disorder, an inflammatory disorder, a fibrotic disorder or a metabolic disorder.